Montelukast-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTelukast-Teva (Montelukast-Teva)

Composition:

Active substance: montelukast;

1 film-coated tablet contains 10 mg of montelukast (as montelukast sodium);

Excipients: lactose monohydrate; hydroxypropylcellulose; pregelatinized corn starch; sodium starch glycolate (type A); magnesium stearate; sodium lauryl sulfate;

Coating Opadry 20A23676 Yellow: hypromellose, hydroxypropylcellulose, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: beige, round film-coated tablet, imprinted with "93" on one side and "7426" on the other side, without visible cracks or chips.

Pharmacotherapeutic group. Medicinal products for systemic use in obstructive respiratory diseases. Leukotriene receptor antagonists. ATC code R03DC03.

Pharmacological properties.

Pharmacodynamics.

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released by various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT). The CysLT type 1 receptor (CysLT1) is located in human airways (particularly on airway smooth muscle cells and airway macrophages), as well as on other pro-inflammatory cells (including eosinophils and certain myeloid progenitor cells). The presence of CysLT receptors correlates with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucus secretion, vascular permeability, and eosinophilia. In allergic rhinitis, CysLT protein is released from the nasal mucosa following allergen exposure during both early- and late-phase reactions, and this is associated with symptoms of allergic rhinitis. According to studies, intranasal administration of CysLT leads to increased nasal airway resistance and enhanced symptoms of nasal congestion.

Montelukast, following oral administration, is an active compound that selectively and with high affinity binds to CysLT1 receptors. Clinical studies have shown that montelukast at a dose of 5 mg inhibits bronchoconstriction induced by inhaled LTD4. Bronchodilation is observed within 2 hours after oral administration, and this effect is additive to bronchodilation caused by β-agonists. Treatment with montelukast suppresses both early and late phases of bronchoconstriction induced by antigen stimulation. Compared with placebo, montelukast reduces the number of peripheral blood eosinophils in adult and pediatric patients. In one study, montelukast significantly reduced eosinophil counts in the airways (measured in sputum) and in peripheral blood and improved clinical asthma control.

In studies involving adults, montelukast 10 mg once daily, compared with placebo, demonstrated significant improvement in morning forced expiratory volume in 1 second (FEV1) (change from baseline: 10.4% vs. 2.7%, respectively), morning peak expiratory flow rate (PEFR) (change from baseline: 24.5 L/min vs. 3.3 L/min, respectively), and a significant reduction in total use of β-agonists (change from baseline: –26.1% vs. –4.6%, respectively). Improvement in patient-reported daytime and nighttime asthma symptoms was significantly better than with placebo.

Studies in adults demonstrated montelukast’s ability to complement the clinical effect of inhaled corticosteroids (change (% baseline) for inhaled beclomethasone plus montelukast vs. beclomethasone alone: for FEV1: 5.43% vs. 1.04%; for β-agonist use: –8.70% vs. 2.64%). Compared with inhaled beclomethasone (200 mcg twice daily, spacer device), montelukast showed a more rapid initial response, although over a 12-week study beclomethasone produced a greater average therapeutic effect (% change from baseline for montelukast vs. beclomethasone: for FEV1: 7.49% vs. 13.3%; for β-agonist use: –28.28% vs. –43.89%). However, a greater proportion of patients receiving montelukast achieved a similar clinical response compared with beclomethasone (i.e., improvement in FEV1 of approximately 11% or more from baseline was achieved in 50% of patients receiving beclomethasone, compared with 42% of patients receiving montelukast).

A clinical study was conducted to evaluate montelukast as a symptomatic treatment for seasonal allergic rhinitis in patients aged 15 years and older with asthma and concomitant seasonal allergic rhinitis. In this study, montelukast tablets 10 mg once daily demonstrated statistically significant improvement in the average daily rhinitis symptom score compared with placebo. The average daily rhinitis symptom score is the mean of daytime nasal symptoms (average nasal congestion, rhinorrhea, sneezing, nasal itching) and nighttime symptoms (average nasal congestion upon awakening, difficulty falling asleep, frequency of nocturnal awakenings). Significantly better results were obtained for overall patient and physician assessment of allergic rhinitis treatment compared with placebo. Evaluation of efficacy for asthma treatment was not a primary objective of this study.

In an 8-week study involving children aged 6 to 14 years, montelukast 5 mg once daily significantly improved respiratory function compared with placebo (change from baseline in FEV1: 8.71% vs. 4.16%; change in morning PEFR: 27.9 L/min vs. 17.8 L/min) and reduced the frequency of as-needed β-agonist use (change from baseline: –11.7% vs. +8.2%).

Significant reduction in exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximum decrease in FEV1: 22.33% with montelukast vs. 32.40% with placebo; time to recovery within 5% of baseline FEV1: 44.22 min vs. 60.64 min). This effect was maintained throughout the 12-week study period. Reduction in EIB was also demonstrated in a short-term study in children aged 6 to 14 years (maximum decrease in FEV1: 18.27% vs. 26.11%; time to recovery within 5% of baseline FEV1: 17.76 min vs. 27.98 min). The effect in both studies was demonstrated at the end of treatment with once-daily dosing.

In patients with aspirin sensitivity receiving ongoing therapy with inhaled and/or oral corticosteroids, treatment with montelukast significantly improved asthma control compared with placebo (change from baseline in FEV1: 8.55% vs. –1.74%; change from baseline in total β-agonist use: –27.78% vs. 2.09%).

Pharmacokinetics.

Absorption. Montelukast is rapidly absorbed after oral administration. After a 10 mg film-coated tablet dose administered to adults under fasting conditions, the mean peak plasma concentration (Cmax) was achieved at 3 hours (Tmax). The mean oral bioavailability is 64%. A standard meal does not affect the bioavailability or Cmax of orally administered montelukast. Safety and efficacy were confirmed in clinical trials with the administration of 10 mg film-coated tablets regardless of meal timing.

For 5 mg chewable tablets, the Cmax in adults was reached within 2 hours after administration under fasting conditions. The mean oral bioavailability is 73% and decreases to 63% when administered with a standard meal.

Distribution. Over 99% of montelukast is bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 liters. In animal studies, passage of radiolabeled montelukast across the blood-brain barrier was minimal. In all other tissues, concentrations of radiolabeled material 24 hours after administration were also minimal.

Metabolism. Montelukast is extensively metabolized. In studies using therapeutic doses, metabolite concentrations of montelukast in steady-state plasma in adults and pediatric patients were not detectable.

Cytochrome P450 2C8 is the primary enzyme involved in the metabolism of montelukast. Additionally, cytochromes CYP 3A4 and 2C9 play a minor role in montelukast metabolism, although itraconazole (a CYP 3A4 inhibitor) did not alter the pharmacokinetic parameters of montelukast in healthy volunteers receiving 10 mg montelukast daily. In vitro studies using human liver microsomes showed that therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Excretion. The plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration of isotopically labeled montelukast, 86% is excreted in feces within 5 days and less than 0.2% in urine. Combined with the oral bioavailability of montelukast, this indicates that montelukast and its metabolites are almost entirely eliminated via bile.

Pharmacokinetics in specific patient populations. Dose adjustment is not required for patients with mild or moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are eliminated via bile, dose adjustment in patients with renal impairment is not considered necessary. Data on the pharmacokinetic profile of montelukast in patients with severe hepatic impairment (Child–Pugh score >9) are lacking.

Administration of high doses of montelukast (20 and 60 times the recommended adult dose) was associated with decreased plasma theophylline concentrations. This effect is not observed with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

Adjunctive treatment of bronchial asthma in patients with mild to moderate persistent asthma that is not adequately controlled with inhaled corticosteroids, and in patients with inadequate clinical control of asthma using short-acting β-adrenergic agonists as needed. In patients with asthma, Montelukast-Teva also relieves symptoms of seasonal allergic rhinitis.

Prevention of asthma in which bronchospasm induced by physical exertion is the predominant component.

Relief of symptoms of seasonal and perennial allergic rhinitis. The risk of developing neuropsychiatric symptoms in patients with allergic rhinitis may outweigh the benefit of Montelukast-Teva; therefore, Montelukast-Teva should be used as a reserve medication in patients with inadequate response to or intolerance of alternative therapies.

Contraindications.

Hypersensitivity to montelukast or to any component of the medicinal product.

Age under 15 years (for the 10 mg dose).

Interaction with other medicinal products and other forms of interaction.

Montelukast-Teva may be administered concomitantly with other medicinal products commonly used for the prevention or long-term treatment of asthma. In drug interaction studies, the recommended dose of montelukast had no clinically significant effect on the pharmacokinetics of the following medicinal products: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients who were concurrently taking phenobarbital, the area under the concentration-time curve (AUC) for montelukast decreased by approximately 40%. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution is advised, especially in children, when montelukast is administered concomitantly with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital, and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, clinical drug interaction studies involving montelukast and rosiglitazone (a drug metabolized by CYP 2C8) demonstrated that montelukast is not an inhibitor of CYP 2C8 in vivo. Thus, montelukast does not significantly affect the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

In vitro studies have established that montelukast is a substrate of CYP 2C8 and, to a lesser extent, of CYP 2C9 and 3A4. In a clinical drug interaction study, coadministration of montelukast with gemfibrozil (an inhibitor of CYP 2C8 and 2C9) increased systemic exposure to montelukast by 4.4-fold. When montelukast is used concomitantly with gemfibrozil or other potent inhibitors of CYP 2C8, dose adjustment of montelukast is not required; however, physicians should be aware of the increased risk of adverse reactions.

Based on in vitro data, clinically significant interactions with less potent inhibitors of CYP 2C8 (e.g., trimethoprim) are not expected. Concomitant administration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, did not result in a significant increase in systemic exposure to montelukast.

Special precautions for use

Patients should be advised that Montelukast-Teva for oral use must never be used for the treatment of acute asthma attacks, and that they should always have an appropriate rescue medication available. In acute attacks, short-acting inhaled β-agonists should be used. Patients should seek immediate medical advice if they require greater than usual amounts of short-acting β-agonist inhalations.

Montelukast should not be used to abruptly displace inhaled or oral corticosteroid therapy.

There are no data confirming that the dose of oral corticosteroids can be reduced when montelukast is coadministered.

In rare cases, patients receiving anti-asthma medications, including montelukast, may develop systemic eosinophilia, sometimes accompanied by clinical features of vasculitis, such as Churg-Strauss syndrome, which is treated with systemic corticosteroids. Such cases have usually (but not always) been associated with a reduction in dose or discontinuation of corticosteroid therapy. The possibility that leukotriene receptor antagonists may be linked to the emergence of Churg-Strauss syndrome cannot be definitively ruled out or confirmed; therefore, physicians should remain vigilant for the development of eosinophilia, vasculitic rash, worsening pulmonary symptoms, or cardiac complications and/or neuropathy in patients. Patients who develop such symptoms should be re-evaluated and their treatment regimen reconsidered.

Montelukast treatment does not permit patients with aspirin-sensitive asthma to use aspirin or other nonsteroidal anti-inflammatory drugs.

Excipients.

Lactose. This medicinal product is contraindicated in patients with rare hereditary conditions of galactose intolerance, absolute lactase deficiency, or glucose-galactose malabsorption.

Sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown any harmful effects on pregnancy or embryonic/fetal development.

Published data from prospective and retrospective cohort studies on the use of montelukast in pregnant women, assessing major congenital malformations in children, do not indicate a risk associated with the use of this medicinal product. However, these studies have methodological limitations, including small sample size, retrospective data collection in some cases, and non-comparable control groups.

Montelukast-Teva may be used during pregnancy only if clearly necessary.

Breastfeeding. Animal studies have shown that montelukast passes into breast milk. It is unknown whether montelukast is excreted in human breast milk. Therefore, Montelukast-Teva may be used during breastfeeding only if clearly necessary.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

Montelukast is not expected to affect the ability to drive vehicles or operate machinery. However, very rare cases of dizziness or somnolence have been reported.

Dosage and Administration

The recommended dose for patients (aged 15 years and older) with asthma or asthma with concomitant seasonal allergic rhinitis is 10 mg (1 tablet) once daily in the evening. The timing of administration may be individually adjusted to relieve symptoms of allergic rhinitis.

General recommendations

The therapeutic effect of Montelukast-Teva on asthma control parameters is observed within 24 hours. Montelukast-Teva may be taken regardless of food intake. Patients should be advised to continue taking Montelukast-Teva even when their asthma symptoms are under control, as well as during asthma exacerbations. Montelukast-Teva should not be used concomitantly with medicinal products containing the same active substance – montelukast.

Special patient groups. Dose adjustment is not required in elderly patients, patients with renal impairment, or patients with mild to moderate hepatic impairment. There is no data available on the use of the drug in patients with severe hepatic impairment. The dosage is the same for men and women.

Use of Montelukast-Teva depending on other asthma treatments

Montelukast-Teva may be added to an existing asthma treatment regimen.

Inhaled corticosteroids. Montelukast-Teva can be used as add-on therapy in patients whose asthma is not adequately controlled with inhaled corticosteroids and as-needed short-acting β-agonists. Inhaled corticosteroids should not be abruptly replaced by Montelukast-Teva (see section "Special precautions").

Children.

For use in children aged 15 years and older. Children under 15 years of age should be given the medicinal product in the form of chewable tablets.

Overdose.

There is no specific information on the treatment of montelukast overdose. In chronic asthma studies, montelukast was administered to adult patients at doses up to 200 mg/day for 22 weeks and up to 900 mg/day in short-term studies for approximately one week, without clinically significant adverse reactions.

Cases of acute montelukast overdose have been reported during post-marketing use and clinical trials. Ingestion of doses exceeding 1000 mg has been reported in adults and children (including a case of ingestion of approximately 61 mg/kg by a 42-month-old child). The clinical and laboratory findings were consistent with the safety profile observed in adult and pediatric patients. In most cases, no adverse reactions were reported. The most commonly observed adverse reactions were consistent with the drug's safety profile and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

It is unknown whether montelukast is eliminated by peritoneal dialysis or hemodialysis.

Adverse reactions

The assessment of montelukast's effects was conducted during clinical studies:

• 10 mg film-coated tablets – a study involving approximately 4000 asthma patients aged 15 years and older;
• 10 mg film-coated tablets – a study involving approximately 400 asthma patients with seasonal allergic rhinitis aged 15 years and older;
• 5 mg chewable tablets – a study involving approximately 1750 asthma patients aged 6 to 14 years.

During clinical studies, the adverse reactions listed below occurred commonly (≥1/100 to <1/10) in patients receiving montelukast treatment and at a higher frequency than in patients receiving placebo.

Table 1

During clinical studies with long-term treatment of a limited number of adult patients (up to 2 years) and children aged 6–14 years (up to 12 months), the safety profile did not change.

Post-marketing period

The adverse reactions listed below have been reported during the post-marketing period. The frequency of adverse reactions is based on data from relevant clinical studies and classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).

Infections and infestations: very common – upper respiratory tract infection.

Blood and lymphatic system disorders: rare – tendency to bleed; very rare – thrombocytopenia.

Immune system disorders: uncommon – hypersensitivity reactions, including anaphylaxis; very rare – hepatic eosinophilic infiltration.

Psychiatric disorders: uncommon – sleep disorders, including nightmares, insomnia, somnambulism, anxiety, agitation, including aggressive behavior or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremorc); rare – attention disorders, memory impairment, tic; very rare – hallucinations, disorientation, suicidal thoughts and behavior (suicidality), obsessive-compulsive symptoms, dysphemia.

Nervous system disorders: uncommon – dizziness, drowsiness, paresthesia/hypoesthesia, convulsions.

Cardiac disorders: rare – palpitations.

Respiratory, thoracic and mediastinal disorders: uncommon – epistaxis; very rare – Churg-Strauss syndrome (see section "Special precautions"), pulmonary eosinophilia.

Gastrointestinal disorders: common – diarrheab, nausea b, vomiting b; uncommon – dry mouth, dyspepsia.

Hepatobiliary disorders: common – increased serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]); very rare – hepatitis (including cholestatic, hepatocellular, and mixed liver injury).

Skin and subcutaneous tissue disorders: common – rashb; uncommon – bruising, urticaria, pruritus; rare – angioedema; very rare – erythema nodosum, erythema multiforme.

Musculoskeletal and connective tissue disorders: uncommon – arthralgia, myalgia, including muscle cramps.

Renal and urinary disorders: uncommon – enuresis in children.

General disorders: common – pyrexiab; uncommon – asthenia/fatigue, malaise, edema.

a This adverse reaction was observed with a "very common" frequency in patients receiving montelukast and in patients receiving placebo in clinical studies.

b This adverse reaction was observed with a "common" frequency in patients receiving montelukast and in patients receiving placebo in clinical studies.

c Frequency: "rare".

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep the blister in the cardboard box to protect from light.

Packaging. 7 tablets per blister, 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer: Teva Pharmaceuticals Poland Sp. z o.o.

Manufacturer's address and place of business.

80 Mogilska Street, 31-546 Kraków, Poland.